EPOC Terapia Dual Centro Médico Imbanaco Carlos E. Salgado T.

Presentación del tema: "EPOC Terapia Dual Centro Médico Imbanaco Carlos E. Salgado T."— Transcripción de la presentación:

1 EPOC Terapia Dual Centro Médico Imbanaco Carlos E. Salgado T.
Cali - Colombia Terapia Dual

2 Conflictos de interés Conferencista y/o Miembro de Comités Asesores de Astrazeneca, Biotoscana, Boeheringer Ingelheim, GlaxoSmithKline, MSD, Novartis, Pfizer, Reckitt y Takeda por los cuales he recibido honorarios No vínculos laborales con el sector público ni con la industria farmacéutica

3 Químicos Ocupacionales
EPOC: Patogénesis Humo de Cigarrillo Químicos Ocupacionales Polución Externa Polución Interna Compromiso Respiratorio Respuesta Inflamatoria Compromiso Sistémico Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014:

4 Hiperplasia glandular
EPOC: Patogénesis Respiratorio Fibrosis p/bronquial Destrucción alveolar Hiperplasia glandular   Flujo espiratorio Atrapamiento Aire Inflamación pulmonar Disnea  Calidad de vida Insulto Muerte Inflamación sistémica Exacerbaciones Sistémico Pérdida de peso Atrofia/Disf. muscular Enfermedad CV Osteoporosis  Medula ósea Depresión  Capacidad ejercicio

5 EPOC: Cambios anatómicos
Fibrosis peribronquial Destrucción alveolar Hiperplasia glandular Cambios Estáticos Resistencia de vía aérea Retractilidad elástica Tono Colinérgico  Cambios Dinámicos  Flujo espiratorio Atrapamiento Aire

6 Hiperplasia glandular
EPOC: Patogénesis Respiratorio Fibrosis p/bronquial Destrucción alveolar Hiperplasia glandular   Flujo espiratorio Atrapamiento Aire Inflamación pulmonar Disnea  Calidad de vida Insulto Muerte Inflamación sistémica Sistémico Exacerbaciones Pérdida de peso Atrofia/Disf. muscular Enfermedad CV Osteoporosis  Medula ósea Depresión  Capacidad ejercicio

7 Exacerbaciones frecuentes
¿ Cual es la importancia de las exacerbaciones ? Exacerbaciones frecuentes Efectos en Síntomas y Función Pulmonar Pobre calidad de vida Rápida caída de función pulmonar Altos Costos Socio-económicos Mayor mortalidad Reference Wedzicha JA, Seemungal TA. Lancet. 2007;370:786–96. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014:

8 Indicadores de riesgo de exacerbaciones: Severidad GOLD
1.6 1.9 2.3 0.5 1.0 1.5 2.0 2.5 >60% 40%-59% <40% % VEF1 Esperado Exacerbaciones por año Results based on a cross-sectional observational study of ambulatory COPD patients in Spain. General practitioners (N=201) completed a questionnaire on COPD characteristics of 1001 patients between October 1994 and May 1995. An exacerbation was defined as an increase in dyspnea, sputum volume, and/or sputum purulence. Miravitlles M et al. Respir Med 1999;93:

9 A Mayor Obstrucción  Mayor Frecuencia
Indicadores de riesgo de exacerbaciones: Severidad GOLD ECLIPSE: Pacientes con ≥2 exacerbaciones durante primer año del estudio. EPOC grave % Pacientes Exacerbaciones frecuentes ECLIPSE: Pacientes con>2 exacerbaciones en el primer año de estudio No sólo los pacientes con EPOC grave experimentanexacerbaciones con mayor frecuencia. Aquí se observa el porcentaje de pacientes que experimentaron exacerbaciones frecuentes (>2 en el primer año de estudio) por la clasificación GOLD VEF1 de la EPOC; 33% de los pacientes en GOLD 3 y 47% de los pacientes en GOLD 4 del estudio ECLIPSE fueron exacerbadores frecuentes. Los pacientes con ≥2 exacerbaciones por año representan un fenotipo distinto de “exacerbación frecuente” y se relacionaron con más exacerbaciones y enfermedad más grave. En el estudio, el mejor predictor de una exacerbación fue el antecedente de exacerbaciones previas. Los pacientes reclutados en el estudio ECLIPSE tenían tenían EPOC GOLD 2 – 4, algunos de los cuales tenían síntomas de bronquitis crónica. Referencia: Hurst JR, et al. Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease. N Engl J Med. 2010;363: A Mayor Obstrucción  Mayor Frecuencia Hurst JR, et al. N Engl J Med. 2010;363:

10 Indicadores de riesgo de exacerbaciones: Severidad GOLD
«Riesgo» en EPOC: Datos de los brazos placebo de estudios TORCH, Uplift y Eclipse GOLD Exacerbaciones (por año) Hospitalizaciones (por año) Mortalidad a 3 años GOLD 1 Leve ? GOLD 2 Moderado 0,7 – 0,9 0,11 – 0,20 11% GOLD 3 Severo 1,1 – 1,3 0,25 – 0,30 15% GOLD 4 Muy Severo 1,2 – 2,0 0,40 – 0,54 24%

11 Indicadores de riesgo de exacerbaciones: Historia de Exacerbaciones
Hurst JR, Vestbo J, Anzueto A et al. N Engl J Med 2010;363: Indicadores de riesgo de exacerbaciones: Historia de Exacerbaciones 71% de los exacerbadores frecuentes en 1° y 2° año, lo fueron en el 3° año 74% de los No Exacerbadores en 1° y 2° año, no tuvieron exacerbaciones el 3° año Año 2 Año 3 Porcentaje Porcentaje Año 1 Porcentaje 1 1 ≥2 ≥2 Reference Hurst JR, et al. N Engl J Med 2010;363:1128–38. Exacerbaciones/año Porcentaje Porcentaje 1 ≥2 1 1 1679 pacientes con EPOC completaron el estudio ≥2 ≥2

12 Indicadores de riesgo de exacerbaciones: Historia de Exacerbaciones
Adaptado de Hurst JR, Vestbo J, Anzueto A et al. N Engl J Med 2010;363: Indicadores de riesgo de exacerbaciones: Historia de Exacerbaciones ¿Hubo en el último año algún episodio que requirió el uso de antibióticos y/o corticoides u hospitalización? Si la respuesta es Afirmativa, el riesgo de experimentar 2 o más exacerbaciones en el próximo año es 5.72 mayor que si la respuesta es Negativa (p<0.001) Speaker notes ECLIPSE demonstrated that the best predictor of future frequent exacerbaciones was a history of exacerbaciones in the previous year (based on patient recall). Thus specifically, asking patients whether they , in the previous year, have experienced a flare-up treated with either antibiotics and/or oral steroids, or leading to hospital admission could help to identify patients with an increased risk of future exacerbaciones. The term ‘flare-up’ may be more useful than ‘exacerbaciones’ when questioning patients about their COPD. This approach may be used to identify patients who are suitable for additional treatment to reduce exacerbaciones. Reference Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in Chronic Obstructive Pulmonary Disease. N Engl J Med 2010;363:

13 Indicadores de riesgo de exacerbaciones
Severidad de obstrucción en Espirometría GOLD Historia de Exacerbaciones Frecuentes

14 Objetivos de manejo Estrategias de manejo

15 EPOC: Objetivos de Manejo
Calidad de Vida Normal Síntomas EPOC Riesgo Se ilustra de manera general los conceptos de Calidad de Vida y Sobrevida como objetivos generales de la práctica de la medicina. 20 40 60 80 Edad (años)

16 ✖ EPOC: Objetivos de Manejo Respiratorio Sistémico Insulto Inflamación
pulmonar Disnea  Calidad de vida Insulto Muerte ✖ Inflamación sistémica Exacerbaciones Sistémico  Capacidad ejercicio

17 EPOC: Estrategias de Manejo
Calidad de Vida Edad (años) 40 20 60 80 Normal EPOC Síntomas Riesgo B/dilatadores Ejercicio (RR) Oxígeno Cirugía Mejorar entorno B/dilatadores Ejercicio (RR) C/inhalados PD4 Oxígeno Se ilustra de manera general los conceptos de Calidad de Vida y Sobrevida como objetivos generales de la práctica de la medicina.

18 EPOC: Efectos de los Broncodilatadores
Mejoran VEF1 y atrapamiento de aire Mejoran capacidad de ejercicio Mejoran disnea y calidad de vida Mejoran frecuencia y severidad de exacerbaciones Mejoran frecuencia de hospitalizaciones Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014:

19 Outcomes are correlated with mean change from baseline in trough FEV1
Average ΔFEV1 (mL) Category centred value of ΔFEV1 (ml) TDI (n=2,781) ΔSGRQ (n=3,141) Exacerbation rate/year (n=3,158) -500, -50 -275 1.44 -3.15 0.63 -50,50 1.31 -3.17 0.58 50,150 100 1.79 -3.84 0.61 150,250 200 2.12 -5.84 0.51 250,500 375 2.68 -7.38 0.38 Conclusions These results suggest that larger improvements in FEV1 with long-acting bronchodilator therapy are likely to be associated with larger patient-centred benefits across a range of outcomes. Results 3313 patients with non-missing values of relevant variables were analysed, excluding extreme values of DFEV1 (outside 6500 ml). TDI and DSGRQ at 12 weeks improved and exacerbation rate declined with increasing positive DFEV1 (all p<0.001) (see Abstract P148 Table 1). Individual-level correlations were weak (0.06e0.18), reflecting the large variability in the outcomes, but cohort-level correlations were strong (0.76e0.93). Results for the proportion of patients demonstrating an improvement of at least the minimal clinically important difference (MCID) for TDI and SGRQ followed a similar pattern to the meaned data. In general, adjustments for baseline covariates, including level of airway obstruction, had little impact on the relationship between DFEV1 and outcomes. TDI and ΔSGRQ at 12 weeks improved with increasing positive ΔFEV1 (all p<p0.001) Individual-level correlations. r= Cohort-level correlations: r= Jones PW. Thorax 2010;65 (suppl 4): A141

20 ¡ Pretender broncodilatación óptima es una Buena Idea !
¿Qué hemos dicho? La obstrucción del flujo aéreo es uno de los determinantes de Disnea, Calidad de vida, Frecuencia y Severidad de Exacerbaciones La Frecuencia y Severidad de las Exacerbaciones es uno de los determinantes del pronóstico La broncodilatación mejora Disnea, Calidad de vida y Exacerbaciones ¡ Pretender broncodilatación óptima es una Buena Idea !

21 ¿ Cómo lograr Broncodilatación óptima ?

22 Ganglio Parasimpático
Control del Tono Bronquial Ganglio Parasimpático Nervio Vago Nervio Parasimpático Posgangliónico M2 (-) M3 (+) M1 (+) N (+) ACh SNC Sistema Simpático Sistema Parasimpático E Médula adrenal Vaso bronquial ß2R NE Ganglio Simpático ß2R Antimuscarínicos Disminuyen Tono Bronquial Las vías aéreas normales tienen un leve grado de “tono bronquial” sin efectos significativos sobre el flujo aéreo. En EPOC, las vías están irreversiblemente estrechadas lo cual hace que el “tono bronquial” tenga efecto significativo (razones geométricas). Habrá entonces efecto perceptible sobre el flujo aéreo al liberar ese “tono” con medicamentos anticolinérgicos. Estos medicamentos, además tienen efecto sobre la secreción mucoide. Receptores: M1: Ganglio parasimpático. Al bloquearlo, se reduce la broncoconstricción M2: Terminales colinérgicas. Inhiben la liberación de AcH (Son autoreceptores) M3: Vías aéreas: Mediadores de la broncoconstricción y la hipersecreción mucoide. (Pulmonary Pharmacology & Therapeutics 23 (2010) 257e267) The airways are innervated by postganglionic, parasympathetic- cholinergic nerves. These nerves release the neurotransmitter acetylcholine (ACh) which regulates muscle tone, bronchoconstriction of small bronchi and bronchioles and airway resistance in larger, cartilaginous airways. Three subtypes of muscarinic receptors are expressed in the human lung (M1, M2 and M3) [7] and are activated at the level of the target cells, such as bronchial smooth muscle and goblet cells [8]. Bronchoconstriction is mediated by the activation of M1 and M3 receptors while inhibitory M2 receptors limit ACh release by negative feedback mechanisms to the M1 and M3 receptors. M2 receptors, abundant on bronchial smooth muscle, also cause indirect contraction of human bronchus by reversing sympathetically mediated relaxation [9]. Conversely, activation of b2-adrenoceptors (b2-ARs), which are abundantly expressed on human airway smooth muscle, stimulates adenylyl cyclase activity, which increases intracellular cyclic adenosine monophosphate (cAMP) and leads to smooth muscle relaxation [10]. There appear to be few direct sympathetic nerve connections to the airways but b2-ARs are instead affected by systemically circulating adrenaline. Bronchodilation may, therefore, be obtained either by directly relaxing the smooth muscle through stimulation of the b2-ARs with b2-agonists, or by inhibiting the action of ACh at muscarinic receptors with muscarinic antagonists, indirectly leading to smooth muscle relaxation (Fig. 1) [11,12]. It therefore seems reasonable to postulate that targeting bronchoconstriction through two distinct mechanisms (anticholinergic and sympathomimetic) should maximize the bronchodilator response and help to overcome inter- and intra-patient variability in bronchomotor tone associated with COPD [19]. The nature of interaction between the two systems is not yet fully understood but there is enough evidence to suggest that combining b2-agonists and anticholinergic agents is pharmaco- logically useful for two reasons [19,21,37]: The addition of a b2-agonist decreases the release of ACh, through the modulation of cholinergic neurotransmission by prejunctional b2-ARs, and thereby amplifies the bronchial smooth muscle relaxation induced by the muscarinic antagonist. The addition of a muscarinic antagonist can reduce bronchoconstrictor effects of ACh, whose release has been modified by the b2-agonist, and thereby amplify the bronchodilation elicited by the b2-agonist through the direct stimulation of smooth muscle b2-ARs [37]. Preclinical data on combinations of b2-agonists and muscarinic antagonists are still rare and it is unclear whether additive or synergistic interactions occur. However, data from a study in anaesthetized artificially ventilated normal and actively sensitized guinea pigs provided clear evidence of a positive interaction between tiotropium and the new LABA carmoterol in controlling the bronchoconstriction elicited by different challenges. In the presence of doses of tiotropium ineffective per se, the median effective dose (ED50) values of carmoterol were significantly reduced by 5 to over 30 times, depending on the challenge. Interestingly, even parameters not directly linked to airway smooth muscle relaxation such as thromboxane A2 release and survival time were significantly modified by the combination. Further research is needed to confirm the presence and nature of pharmacological interactions between LABAs and LAMAs. ß2 Agonistas Broncodilatan

23 Ganglio Parasimpático
Control del Tono Bronquial SNC PKA (activa) PK (inactiva) Broncodilatación β2-agonista Gs AC β2R ATP cAMP Ganglio Parasimpático Nervio Vago Nervio Parasimpático Posgangliónico M2 (-) M3 (+) M1 (+) N (+) ACh (Pulmonary Pharmacology & Therapeutics 23 (2010) 257e267) The airways are innervated by postganglionic, parasympathetic- cholinergic nerves. These nerves release the neurotransmitter acetylcholine (ACh) which regulates muscle tone, bronchoconstriction of small bronchi and bronchioles and airway resistance in larger, cartilaginous airways. Three subtypes of muscarinic receptors are expressed in the human lung (M1, M2 and M3) [7] and are activated at the level of the target cells, such as bronchial smooth muscle and goblet cells [8]. Bronchoconstriction is mediated by the activation of M1 and M3 receptors while inhibitory M2 receptors limit ACh release by negative feedback mechanisms to the M1 and M3 receptors. M2 receptors, abundant on bronchial smooth muscle, also cause indirect contraction of human bronchus by reversing sympathetically mediated relaxation [9]. Conversely, activation of b2-adrenoceptors (b2-ARs), which are abundantly expressed on human airway smooth muscle, stimulates adenylyl cyclase activity, which increases intracellular cyclic adenosine monophosphate (cAMP) and leads to smooth muscle relaxation [10]. There appear to be few direct sympathetic nerve connections to the airways but b2-ARs are instead affected by systemically circulating adrenaline. Bronchodilation may, therefore, be obtained either by directly relaxing the smooth muscle through stimulation of the b2-ARs with b2-agonists, or by inhibiting the action of ACh at muscarinic receptors with muscarinic antagonists, indirectly leading to smooth muscle relaxation (Fig. 1) [11,12]. It therefore seems reasonable to postulate that targeting bronchoconstriction through two distinct mechanisms (anticholinergic and sympathomimetic) should maximize the bronchodilator response and help to overcome inter- and intra-patient variability in bronchomotor tone associated with COPD [19]. The nature of interaction between the two systems is not yet fully understood but there is enough evidence to suggest that combining b2-agonists and anticholinergic agents is pharmaco- logically useful for two reasons [19,21,37]: The addition of a b2-agonist decreases the release of ACh, through the modulation of cholinergic neurotransmission by prejunctional b2-ARs, and thereby amplifies the bronchial smooth muscle relaxation induced by the muscarinic antagonist. The addition of a muscarinic antagonist can reduce bronchoconstrictor effects of ACh, whose release has been modified by the b2-agonist, and thereby amplify the bronchodilation elicited by the b2-agonist through the direct stimulation of smooth muscle b2-ARs [37]. Preclinical data on combinations of b2-agonists and muscarinic antagonists are still rare and it is unclear whether additive or synergistic interactions occur. However, data from a study in anaesthetized artificially ventilated normal and actively sensitized guinea pigs provided clear evidence of a positive interaction between tiotropium and the new LABA carmoterol in controlling the bronchoconstriction elicited by different challenges. In the presence of doses of tiotropium ineffective per se, the median effective dose (ED50) values of carmoterol were significantly reduced by 5 to over 30 times, depending on the challenge. Interestingly, even parameters not directly linked to airway smooth muscle relaxation such as thromboxane A2 release and survival time were significantly modified by the combination. Further research is needed to confirm the presence and nature of pharmacological interactions between LABAs and LAMAs. Anti Colinérgicos ß2 Agonistas

24 Control del Tono Bronquial
β2-agonista ACh ß2-receptor Epinefrina Antimuscarínicos M1 M1 M3 M3 M3 M3 M3 ß2-receptor

25 Broncodilatadores Categoría Duración ß2 Agonistas Anti Colinérgicos
Corta acción 6 horas Salbutamol Fenoterol Terbutalina Ipratropio Larga acción 12 horas Salmeterol Formoterol Aclinidio Darotropio Ultralarga acción 24 horas Indacaterol Vilanterol Olodaterol Carmoterol Tiotropio Glicopirronio Umeclidinio

26 SABA + SAMA SABA SAMA o CHEST 1997; 112:1514-21
Albuterol + Ipratropio Ipratropio Albuterol Study objective: We compared the long-term safety and eficacy of the combination ipratropium bromide (IB) and albuterol sulfate (ALB) inhalation solution with that of each separate componentusingthre-times-dailyadministration. Design:Usinga paraleldesign,we randomized patients to receive 3.0mg ALB, 0.5 mg IB, or the combination by small-volume nebulizer(SVN) for 85 days.Subjectswere allowedtouse uptotwo extradosesofstudymedicationdailyforcontrolofsymptomson an as-neededbasis.Themain eficacyevaluationwas theacutepulmonaryfunctionresponsetoan aerosolofthemaintenance studymedicationover thecourse oftheinvestigation.Physicianglobalevaluation,subjectquality oflifeassessments,COPD symptomscores,andtwice-dailypeakexpiratoryflowrate(PEFR) were alsoassessedover thestudyperiod. Seting:Twenty-fivecenters participatedintheinvestigation. Patients:We studied652patientswithmoderatetosevere COPD. Measurementsandresults:Overthecourse ofthestudy,theacutespirometricresponseand eveningPEFRvalueswiththeSVNcombinationofIBplusALBwere statisticalysignificantly bettercomparedtoALBor IBalone.Thequalityoflifescores,physicianglobalevaluations, symptomscores,andmorningPEFRscoreswere unchangedoverthedurationofthestudyinal treatmentgroups.Therewas no significantdifferenceinadverseeventsinthethreetreatment groups. Conclusions:InpatientswithCOPD,maintenance SVN therapywithIB andALB providesbetter bronchodilationthaneithertherapyalonewithoutincreasingsideefects. (CHEST1997;112: ) CHEST 1997; 112:

27 SABA + SAMA SABA SAMA o CHEST 1999; 115:966–971
Albuterol + Ipratropio Ipratropio Albuterol Study objectives: To determine whether the combination of ipratropium bromide and albuterol results in greater and more consistent pulmonary function test (PFT) response rates than ipratropium bromide or albuterol alone in patients with COPD. Design: Retrospective review of two recently completed 3-month, randomized, double-blind, parallel, multicenter, phase III trials. Setting: Outpatient. Patients: A total of 1,067 stable patients with COPD. Interventions: Ipratropium bromide (36 􏰁g qid), albuterol base (180 􏰁g qid), or an equivalent combination of ipratropium bromide and albuterol sulfate (42 􏰁g and 240 􏰁g qid, respectively). Measurements and results: PFT response rates were analyzed using 12% and 15% increases in FEV1 compared with baseline values and were measured in the various treatment groups on days 1, 29, 57, and 85 in these trials. Regardless of whether a 12% or a 15% increase in FEV1 was used to define a positive response, an equivalent combination of ipratropium bromide and albuterol sulfate was superior to the individual agents (p < 0.05; all comparisons within 30 min). In addition, a 15% or more increase in FEV1 was seen in > 80% of patients who received the combination of ipratropium and albuterol sulfate during the initial PFT and continued to be observed 3 months after initial testing. Conclusions: Use of a combination of ipratropium bromide and albuterol sulfate is superior to the individual agents in identifying PFT reversibility in patients with COPD. (CHEST 1999; 115:966–971) CHEST 1999; 115:966–971

28 SABA + SAMA SABA SAMA o CHEST 1999; 115:966–971 Albuterol + Ipratropio

29 SABA + SAMA SABA SAMA o CHEST 1999; 115:635-641
Study objective: To conduct a post hoc pharmacoeconomic evaluation of two double-blind, randomized, prospective, parallel group studies comparing the long-term efficacy and safety of ipratropium combined with albuterol in a single inhalational canister against either bronchodilator agent alone in patients with COPD. Patients: One thousand sixty-seven patients with COPD. Methods: The dose of each bronchodilator was two puffs four times a day (42 􏰁g of ipratropium bromide, 240 􏰁g of albuterol sulfate). Pulmonary function testing was performed on days 1, 29, 57, and 85 of treatment. Outcomes, health-care resource consumption, and costs were compared for the three treatment groups over the 85-day study period. A total of 1,067 patients were randomized in the two studies (albuterol alone, n 􏰇 347; ipratropium alone, n 􏰇 362; albuterol plus ipratropium, n 􏰇 358). Results: Improvement in FEV1 and area under the FEV1 response-time curve from time 0 to 4 h (FEV1AUC0 – 4) was significantly greater for the combination of albuterol plus ipratropium than either agent alone on all test days. Compared with albuterol, patients receiving ipratropium and ipratropium plus albuterol experienced significantly fewer COPD exacerbations and patient-days of exacerbation. In addition, the increased frequency of exacerbations observed in the albuterol group was associated with a significant increase in the number of patient hospital days and antibiotic and corticosteroid use. As a result, the total cost of treatment over the study period was significantly less for ipratropium ($156 per patient) and ipratropium plus albuterol ($197 per patient) than for albuterol ($269 per patient). Increased cost-effectiveness, defined as total estimated treatment cost per mean change in FEV1AUC0 – 4, was observed in both treatment arms containing ipratropium. Conclusions: The inclusion of ipratropium in a pharmacologic treatment regimen is associated with a lower rate of exacerbations in COPD. The result is lower total treatment costs and improved cost-effectiveness. (CHEST 1999; 115:635–641) CHEST 1999; 115:

30 Change from Baseline in
LABA SAMA n = 411 (VEF1 < 65% Pred.) ALL PATIENTS Day 1 0.5 0.4 * Change from Baseline in FEV1 (L) 0.3 Salmeterol 0.2 Ipratropio Study objectives: To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled 􏰀2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD. Design: A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial. Setting: Multiple sites at clinics and university medical centers throughout the United States. Patients: Four hundred eleven symptomatic patients with COPD with FEV1 < 65% predicted and no clinically significant concurrent disease. Interventions: Comparison of inhaled salmeterol (42 􏰁g twice daily), inhaled ipratropium bromide (36 􏰁g four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks. Results: Salmeterol xinafoate was significantly (p < ) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments. Conclusions: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD. (CHEST 1999; 115:957–965) 0.1 TIME (HOURS) Placebo 1 2 3 4 5 6 7 8 9 10 11 12 13 Mahler D, CHEST 1999; 115:957–965

31 Change from Baseline in
LABA SAMA n = 411 (VEF1 < 65% Pred.) ALL PATIENTS Day 84 0.5 0.4 * Change from Baseline in FEV1 (L) * * * * * * 0.3 * * Salmeterol 0.2 Ipratropio Study objectives: To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled 􏰀2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD. Design: A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial. Setting: Multiple sites at clinics and university medical centers throughout the United States. Patients: Four hundred eleven symptomatic patients with COPD with FEV1 < 65% predicted and no clinically significant concurrent disease. Interventions: Comparison of inhaled salmeterol (42 􏰁g twice daily), inhaled ipratropium bromide (36 􏰁g four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks. Results: Salmeterol xinafoate was significantly (p < ) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments. Conclusions: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD. (CHEST 1999; 115:957–965) 0.1 TIME (HOURS) Placebo 1 2 3 4 5 6 7 8 9 10 11 12 13 Mahler D, CHEST 1999; 115:957–965

32 LABA + SAMA SABA + SAMA Formoterol / Ipratropio
n = 172 (VEF1 < 65% Pred.) 3 sem Formoterol / Ipratropio Formoterol / Ipratropio Salbutamol / Ipratropio Study objectives: To compare the efficacy of adding formoterol or salbutamol to regular ipratropium bromide treatment in COPD patients whose conditions were suboptimally controlled with ipratro- pium bromide alone. Design: A randomized, double-blind, double-dummy, two-period, crossover clinical trial. Setting: Twenty-four clinics and university medical centers in nine countries. Patients: One hundred seventy-two patients with baseline FEV1 < 65% predicted, with FEV1 reversibility to salbutamol not exceeding the normal variability of the measurement, and symptomatic despite regular treatment with ipratropium bromide. Interventions: Each patient received two treatments in random order: either inhaled formoterol dry powder, 12 􏰀g bid, in addition to ipratropium bromide, 40 􏰀g qid for 3 weeks, followed by salbutamol, 200 􏰀g qid, in addition to ipratropium, 40 􏰀g qid for 3 weeks, or vice versa. Measurements and results: Efficacy end points included morning premedication peak expiratory flow (PEF) during the last week of treatment (primary end point), the area under the curve (AUC) for FEV1 measured for 6 h after morning dose on the last day of treatment, and symptom scores (from daily diary recordings). Morning PEF and the AUC for FEV1 were significantly better for formoterol/ ipratropium than for salbutamol/ipratropium (p 􏰈 and p < , respectively). The formot- erol/ipratropium combination also induced a greater improvement in mean total symptom scores (p 􏰈 ). The safety profile of the two treatments was comparable. Conclusions: In COPD patients requiring combination bronchodilator treatment, the addition of formoterol to regular ipratropium treatment is more effective than the addition of salbutamol. (CHEST 2001; 119:1347–1356) CHEST 2001; 119:

33 LABA + LAMA LAMA Formoterol and Tiotropium Compared With Tiotropium Alone for Treatment of COPD Donald P. Tashkin1 James Pearle2 Domenic Iezzoni,3† and Santosh T. Varghese3 1David Geffen School of Medicine at UCLA, Los Angeles, California, USA 2Western Pulmonary Medical Group, Fullerton, California, USA 3Schering-Plough, Kenilworth, New Jersey, USA ABSTRACT Combined use of β2-agonists and anticholinergic bronchodilators may have complementary benefits in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to compare combination treatment with formoterol (FORM) plus tiotropium (TIO) versus treatment with TIO alone in patients with COPD. In this active-controlled, double-blind, multicenter trial, a total of 255 subjects with diagnosed COPD were randomized to 12 weeks of either a combination of FORM 12 μg twice-daily plus TIO 18 μg once-daily in the morning (QD AM) or monotherapy with TIO 18 μg QD AM. The primary efficacy variable was the area under the curve for forced expiratory volume in 1 second measured 0 to 4 hours after AM dosing (FEV1 AUC0−4h). Significantly greater improvements in the FEV1 AUC0−4h were seen with FORM + TIO (n = 116) versus TIO (n = 124) at all time points. The increase in FEV1 5 minutes after the first dose was 180 mL with FORM + TIO versus 40 mL with TIO (p < 0.001). At endpoint, FEV1 AUC0−4h increased 340 mL with FORM + TIO versus 170 mL with TIO (p < 0.001). Improvements in trough FEV1 with FORM + TIO versus TIO were 180 mL and 100 mL, respectively (p < 0.01). Significantly greater reductions from baseline in symptom scores (p < 0.05) and daytime albuterol use (p < 0.04) were seen at endpoint with combination FORM + TIO versus TIO monotherapy. Both treatments were well tolerated. This study demonstrated that concurrent treatment with FORM + TIO results in greater therapeutic benefits than TIO alone. Tashkin D.,Journal of Chronic Obstructive Pulmonary Disease, :17–25

34 LABA + LAMA LAMA Formoterol and Tiotropium Compared With Tiotropium Alone for Treatment of COPD Donald P. Tashkin1 James Pearle2 Domenic Iezzoni,3† and Santosh T. Varghese3 1David Geffen School of Medicine at UCLA, Los Angeles, California, USA 2Western Pulmonary Medical Group, Fullerton, California, USA 3Schering-Plough, Kenilworth, New Jersey, USA ABSTRACT Combined use of β2-agonists and anticholinergic bronchodilators may have complementary benefits in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to compare combination treatment with formoterol (FORM) plus tiotropium (TIO) versus treatment with TIO alone in patients with COPD. In this active-controlled, double-blind, multicenter trial, a total of 255 subjects with diagnosed COPD were randomized to 12 weeks of either a combination of FORM 12 μg twice-daily plus TIO 18 μg once-daily in the morning (QD AM) or monotherapy with TIO 18 μg QD AM. The primary efficacy variable was the area under the curve for forced expiratory volume in 1 second measured 0 to 4 hours after AM dosing (FEV1 AUC0−4h). Significantly greater improvements in the FEV1 AUC0−4h were seen with FORM + TIO (n = 116) versus TIO (n = 124) at all time points. The increase in FEV1 5 minutes after the first dose was 180 mL with FORM + TIO versus 40 mL with TIO (p < 0.001). At endpoint, FEV1 AUC0−4h increased 340 mL with FORM + TIO versus 170 mL with TIO (p < 0.001). Improvements in trough FEV1 with FORM + TIO versus TIO were 180 mL and 100 mL, respectively (p < 0.01). Significantly greater reductions from baseline in symptom scores (p < 0.05) and daytime albuterol use (p < 0.04) were seen at endpoint with combination FORM + TIO versus TIO monotherapy. Both treatments were well tolerated. This study demonstrated that concurrent treatment with FORM + TIO results in greater therapeutic benefits than TIO alone. Tashkin D.,Journal of Chronic Obstructive Pulmonary Disease, :17–25

35 LABA + LAMA LAMA Indacaterol + Tiotropio / Tiotropio + Placebo
Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison Donald A Mahler,1,2 Anthony D’Urzo,3 Eric D Bateman,4 Serir A O ̈zkan,5 Tracy White,6 Clare Peckitt,7 Cheryl Lassen,7 Benjamin Kramer,6 on behalf of the INTRUST-1 and INTRUST-2 study investigators - Thorax 2012;67:781e788. Mahler DA et all. INTRUST-1 and INTRUST-2 studies:Thorax 2012;67:781e788

36 LABA + LAMA LABA LAMA o J.A. van Noord: Eur Respir J 2005; 26: 214–222
Tiotropio / Formoterol Tiotropio / Formoterol Tiotropio Tiotropio Formoterol Formoterol Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD J.A. van Noord*, J-L. Aumann#, E. Janssens", J.J. Smeets*, J. Verhaert", B. Disse+, A. Mueller+ and P.J.G. Cornelissen+ ABSTRACT: This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 mg q.d., formoterol 12 mg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0–12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12–24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs?day-1, tiotropium 2.41 puffs?day-1, formoterol 2.37 puffs?day-1). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval. J.A. van Noord: Eur Respir J 2005; 26: 214–222

37 Forced expiratory volume in 1 s (FEV1) at all time points on (A) day 7 (B) day 1.
LABA + LAMA LABA n=154 QVA /50 mcg Indacaterol 300 mcg Indacaterol 600 mcg Placebo Day 1 -2 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) FEV1 (L) 1.7 1.6 1.5 1.4 1.3 1.2 Glicopirronio / Indacaterol Indacaterol Placebo ABSTRACT Background This randomised, double-blind, placebo controlled, four-period crossover study assessed the efficacy and safety of once-daily QVA149, a dual bronchodilator consisting of the long-acting b2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237), in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Methods Patients (N1⁄4154) were randomly assigned to receive QVA149 (indacaterol/NVA237) 300/50 mg, indacaterol 300 mg, indacaterol 600 mg, or placebo, once daily for 7 days with a 7-day washout period between each treatment. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) (mean of 23 h 15 min and 23 h 45 min post-dose values) on day 7. Other endpoints included trough FEV1 on day 1, individual time point FEV1 and monitoring and recording of all adverse events. Results A total of 135 (87.7%) patients completed the study (all randomly assigned patients: mean age 61.7 years, 61.4% male, post-bronchodilator FEV1 52.2% predicted, FEV1/forced vital capacity 47.6%). The estimated treatment difference (95% CI) for trough FEV1 on day 7 between QVA149 and placebo was 226 ml (192 to 260; p<0.001). The estimated treatment difference between QVA149 and indacaterol 300 and 600 mg was 123 ml (89 to 157; p<0.001) and 117 ml (83 to 150; p<0.001), respectively. The improvements in mean trough FEV1 exceeded the predefined minimal clinically important differences of 100e140 ml for QVA149 versus placebo and indacaterol. Similar results were observed on day 1. All treatments were well tolerated. Conclusions QVA149 demonstrated rapid and sustained bronchodilation with significant improvements compared with indacaterol monotherapy and placebo in patients with COPD. Clinical trial registration NCT Forced expiratory volume in 1 s (FEV1) at all time points on (A) day 7 (B) day 1. van Noord J A et al. Thorax 2010;65:

38 Forced expiratory volume in 1 s (FEV1) at all time points on (A) day 7 (B) day 1.
LABA + LAMA LABA QVA /50 mcg Day 7 Indacaterol 300 mcg 1.7 Indacaterol 600 mcg Placebo 1.6 Glicopirronio / Indacaterol 1.5 FEV1 (L) Indacaterol 1.4 Forced expiratory volume in 1 s (FEV1) at all time points on (A) day 7 (B) day 1. 1.3 Placebo 1.2 -2 2 4 6 8 10 12 14 16 18 20 22 24 Time (h) van Noord J A et al. Thorax 2010;65:

39 Trough forced expiratory volume in 1 s (FEV1) on (A) day 7 (B) day 1.
LABA + LAMA LABA 1,6 1,5 1,4 1,3 1,2 FEV1 (L) QVA /50 μg (n=140) (n=139) Indacaterol 300 μg (n=138) Indacaterol 600 μg (n=142) Placebo (n=136) 1.512 1.389 1.395 1.286 * # * 1.503 1.378 1.396 1.323 Day 7 Day 1 a b Data are least squares mean±SE; *p< vs placebo; #p< vs indacatero 300 μg and 600 μg Trough forced expiratory volume in 1 s (FEV1) on (A) day 7 (B) day 1. van Noord J A et al. Thorax 2010;65:

40 Primary endpoint: QVA149 vs. indacaterol and glycopyrronium
SHINE: QVA149 significantly improved mean trough FEV1 at Week 26 versus all comparators Primary endpoint: QVA149 vs. indacaterol and glycopyrronium Bateman et al. ERS 2012.

41 Broncodilatadores Duración ß2 Agonistas Anticolinérgicos Corta acción
6 horas Salbutamol Fenoterol Terbutalina Ipratropio Larga acción 12 horas Salmeterol Formoterol Aclidinio Darotropio Ultralarga acción 24 horas Indacaterol Vilanterol Olodaterol Carmoterol Tiotropio Glicopirronio Umeclidinio

42 Evidencia de LAMA’s Tiotropio mejora función pulmonar, calidad de vida, disminuye síntomas y exacerbaciones (frecuencia y severidad) (Evidencia A) Tiotropio mejora efectividad de programa de rehabilitación (Evidencia B) Aclidinio y Glicopirronio tienen efectos similares a Tiotropio en función pulmonar y disnea. Aclidinio tiene duración de 12 horas Tiotropio y Glicopirronio tienen duración de > 24 horas Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014:

43 Evidencia de LABA’s Formoterol y Salmeterol mejoran VEF1, disnea, calidad de vida y frecuencia de exacerbaciones (Evidencia A) Indacaterol mejora disnea, calidad de vida y frecuencia de exacerbaciones (Evidencia B) Indacaterol tiene efecto broncodilatador significativamente mayor que Formoterol y Salmeterol y similar a Tiotropio (Evidencia A) Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014:

44 Tashkin and Ferguson Respiratory Research 2013, 14:49

45 ¡ Pretender broncodilatación óptima es una Buena Idea !
¿Qué más hemos dicho? Mejorar la obstrucción bronquial es deseable en el propósito de mejorar calidad de vida y disminuir los riesgos La mejoría puede lograrse mediante disminución del tono bronquial (Anticolinérgicos) o broncodilatación (β2 agonistas) La combinación de ambos mecanismos es más efectiva que sólo uno de ellos Los broncodilatadores de larga acción son superiores a los de corta acción ¡ Pretender broncodilatación óptima es una Buena Idea !

46 ! Gracias ¡